Granular preparation for MRI

ABSTRACT

The present invention relates to a granular preparation for MRI obtained by granulating a viscosity-increasing agent together with a binder and if necessary, a vehicle, a disintegrant, etc., by the use of a fluidized-bed granulation method, and spraying ferromagnetic particles suspended in an aqueous solution of a viscosity-increasing agent or a binder for coating the granules or incorporating the suspension into he granules at the time of granulation to prepare bulky granules. The granular preparation according to the present invention does not undergo coagulation due to gelling at the time of suspending, and can be instantaneously turned into a suspension which is uniform and viscose by mere stirring. Accordingly, the preparation method is simple and easy. Since it is a solid preparation, stability of the ferromagnetic particle is higher than that of an aqueous dispersion, it is free from the problem of putrefaction by microorganisms and molds and is advantageous from the aspects of transportation and storage space.

DESCRIPTION

1. Technical Field

The present invention relates to contrast agents for MRI (MagneticResonance Imaging).

2. Background Art

Clinical applications of MRI have rapidly developed from the beginningof the 1980's, since its first application in the medical field in theearly 1970's. MRI is now regarded as an important noninvasiveimage-forming technique, comparable with X-rays, computed tomography(X-ray CT) and ultrasonic diagnosis. MRI provides images based onnuclear magnetic resonance signals of protons in tissues of livingorganisms. Since it permits a high freedom in image forming and has highresolution, it was originally considered that contrast agents were notnecessary. However, as clinical experience has been accumulated, certaindrawbacks and limitations of MRI have come to light, and therefore,various contrast agents for MRI have been developed to provide a clearcontrast between the normal tissue and the diseased part.

Contrast agents for MRI are divided into groups of positive contrastagents which intensify signal intensities by shortening the longitudinalrelaxation time of protons, and negative contrast agents which weakensignal intensities by shortening the transverse relaxation time ofprotons. Paramagnetic metal ions belong to the former group, typicalexamples of which include chelating compounds of gadolinium such asmagnebiste.

On the other hand, ferromagnetic particles belong to the latter group.When magnetic particles are administered to a subject orally or perrectum in the MRI diagnosis, artifacts caused by gas or the like in thedigestive tract and peristalsis of the digestive tract can be minimizedby rendering the digestive tract as a dark image. Therefore, the qualityof image diagnosis in the abdominal organs can be enhanced byintensifying the contrast between the digestive tract and the targetorgan (Japanese patent application laid-open (kokai) SHO 61-501633).

Concerning preparations containing ferromagnetic particles, dispersionsprepared by suspending ferromagnetic particles in an aqueous mediumcontaining a viscosity-increasing agent or a surfactant have beenproposed for use with administration by oral route or per rectum(Japanese patent application laid-open (kokai) SHO 61-501633).

However, since dispersions are prepared by diluting with water or withan aqueous medium, they easily putrefy due to propagation ofmicroorganisms such as molds and bacteria, and therefore, the additionof preservatives is needed. In order to inhibit the growth ofmicroorganisms such as molds and bacteria, it is required to addpreservatives in such amounts that the concentration thereof exceeds acertain threshold value. When contract agents of ferromagneticpreparations are used, relatively large amounts of dose, ranging from600 to 1,000 ml, must be administered, and therefore, a problem arisesin that the total uptake of preservatives can exceed the amountpermitted in one day.

In dispersions, most ferromagnetic particles exist as solids suspendedtherein, and a part of ferromagnetic particles exists in a dissolvedstate. Generally speaking, a solid state is more stable than a solutionstate, and therefore, ferromagnetic particles in dispersions areconsidered disadvantageous compared to those in a solid state withregard to stability.

Moreover, dispersions have the drawback that a large space is requiredfor the storage and transportation of the dispersion preparations. Inview of this, granular preparations which are capable of being preparedinto a dispersion upon clinical use are desirable compared topreparations supplied, transported and stored in dispersions.

In an attempt to overcome the above drawbacks, granular preparationscontaining ferromagnetic particles and viscosity-increasing agents haverecently been developed (EP 0409351-A1).

However, in order to prepare a dispersion of a granular preparation inwater or in an aqueous medium, a stirring operation from 15 seconds to60 minutes, preferably 2 to 10 minutes, is needed, which is considerablylaborious and time-consuming. Accordingly, the disclosed granularpreparations are not satisfactory with respect to readiness for use.Moreover, since the granular preparations contain a viscosity-increasingagent, they precipitate and become gelled to form clusters at the bottomof the container, if stirring is insufficient. Once clusters are formed,it is difficult to redisperse this. Furthermore, since such granularpreparations which are slow in becoming hydrated provide a dispersion inwhich swollen particles in a gel state are dispersed in water or in anaqueous medium, they may be difficult to ingest. Therefore, conventionalgranular preparations are not satisfactory in terms of instantpreparation and ease in taking.

Accordingly, an object of the present invention is to provide a contrastagent in a solid form, which is a granular preparation capable of beinginstantly dispersed to provide a homogeneous and viscous dispersion whensuspended in water or in an aqueous medium upon use.

DISCLOSURE OF THE INVENTION

The present invention provides a granular preparation for MRI whichcomprises bulky particles containing a ferromagnetic material and aviscosity-increasing agent.

Due to the bulkiness of the particles, the granular preparationaccording to the present invention is not coagulated by gellation whenit is prepared into a suspension. It instantly provides a uniformviscous suspension upon stirring. Accordingly, the preparation method issimple and easy. Moreover, since it is a solid preparation,ferromagnetic particles are stably carried therein, and putrefaction bymicroorganisms and molds is negligible compared with aqueousdispersions. It is also advantageous in handling, in view of thetransportation and reduced space for storage.

BEST MODE FOR CARRYING OUT THE INVENTION

The ferromagnetic material which is used in the present invention servesas the active component of the contrast agent for MRI. It encompassesnot only ferromagnetic materials, but also ferrimagnetic andsuperparamagnetic materials. A specific example of the ferromagneticmaterials is selected from the group consisting of magnetite (Fe₃ O₄),gamma-ferric oxide (gamma-Fe₂ O₃), cobalt ferrite, nickel ferrite,manganese ferrite and mixtures thereof.

In the present invention, the ferromagnetic material may be incorporatedby itself. However, it is preferred that the ferromagnetic materialfirst be coated with, embedded in, or carried by a nonmagnetic polymerto provide composite particles, and the resulting particles (hereinafterreferred to as ferromagnetic particles) be incorporated into thegranular preparation of the invention.

Examples of the above-described nonmagnetic polymer which is used toprepare ferromagnetic particles include naturally-occurred or syntheticpolymers such as cellulose, its derivatives and polymer latexes. Ofthese, sulfonated styrene-divinylbenzene copolymers (for example,WO86/03920) is particularly preferred.

The ferromagnetic particles are prepared by physically combiningferromagnetic crystals with the polymer latex in the surface of thepolymer particles for carrying the crystals.

The ferromagnetic particles have an average diameter of not more than 50μm and preferably 0.1 to 20 μm.

The amount of the ferromagnetic material or ferromagnetic particlescontained in the granular preparation of the present invention issuitably determined with reference to the expected efficacy of thepreparation, and generally, from about 1 to 10% by weight (hereinafterreferred to simply as %) based on the total weight of the preparation.

The granular preparation of the present invention is characterized bycomprising a viscosity-increasing agent.

The viscosity-increasing agent which is used in the granular preparationof the present invention is soluble in water or swells in the presenceof water. Moreover, the viscosity-increasing agent must be difficult todecompose in a living body and must be physiologically acceptable whenadministered to a living body.

When such a viscosity-increasing agent is used, the inner walls of thedigestive tract are covered by ferromagnetic particles, which render thedigestive tract as a dark image, thereby intensifying the contrastbetween the digestive tract and the target organs.

Examples of the viscosity-increasing agent include cellulosederivatives, magnesium aluminum silicate (Veegum), xanthan gum, and thelike. Specific examples of the cellulose derivatives which are useful asthe viscosity-increasing agent include methylcellulose,carboxymethylcellulose-Na, crystallinecellulose.carboxymethylcellulose-Na, and the like. They may be usedsingly or in combination of two or more.

The viscosity-increasing agent according to the present invention isgenerally incorporated in an amount of 3 to 90%, particularly 15 to 80%,based on the total weight of the preparation.

Furthermore, the granular preparation of the present invention maycontain disintegrants, binders, vehicles and the like in addition to theviscosity-increasing agent.

Examples of the disintegrants include corn starch, carmellose calcium,hydroxypropylcellulose of low substitution degree and cross carmellosesodium. They may be incorporated in amounts of not more than 20%.Generally speaking, it is preferred that they be incorporated in amountsfrom 2 to 10% based on the total weight of the preparation.

Examples of the binders include the above-mentioned viscosity-increasingagents, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and the like. The amounts of the bindersare generally 10% or less, and preferably from 2 to 8%, based on thetotal weight of the preparation.

Examples of the vehicles include corn starch, partly pregelatinizedstarch, lactose and mannitol. The amounts of the vehicles are notparticularly limited. Preferably, they are incorporated in a range from1 to 95%.

When a surfactant is incorporated into the granular preparation of thepresent invention, the suspension property is improved and a homogeneousdispersion is obtained. Examples of the surfactant which will facilitatedispersing of particles include those which are generally employed inthe art, such as polysorbate 80, polyoxyethylene, polyoxypropylenecopolymers, and the like (Japanese patent application laid-open (kokai)SHO 61-501633). They are incorporated in amounts from 0.01 to 15% basedon the total weight of the preparation.

Examples of additives other than those mentioned above includeantioxidants, sweeteners, flavors, colorants, and the like. Specificexamples of the antioxidants include sodium sulfite, sodiumhydrogensulfite, sodium hydrogenthiosulfate, ascorbic acid,thioglycerol, tocopherol, dibutylhydroxytoluene and butylhydroxyanisole.Moreover, the granular preparation may optionally contain suitablesweeteners, flavors, colorants and the like.

It is necessary that the granular preparation according to the presentinvention take the form of bulky particles. The term "bulky particles"means that the particles have a small apparent density. The apparentdensity is preferably not more than 0.4 g/ml, and more preferably from0.1 to 0.4 g/ml.

Generally, the particle diameter of the granular preparation of thepresent invention is preferably in the range of 150 to 1400 μm.Particularly, it is preferred that particles having a diameter of notmore than 150 μm exist in a proportion of not more than 20% of the totalparticles.

The viscosity of an aqueous suspension of the granular preparation ofthe present invention is preferably from 50 to 2000 cp after beingcompletely hydrated.

The granular preparation of the present invention is obtained by agranulation method.

Granulation is an operation of converting a starting material in theform of powder, block, or solution into particles. Methods ofgranulation for preparing medicines are generally divided intodry-granulation methods and wet-granulation methods from the aspects ofmechanism of apparatus and granulating mechanism of starting powders.The dry-granulation methods comprise a compression granulation methodand a melting granulation method.

Among the wet-granulation methods, four methods are widely used: anextrusion granulation method using a cylindrical granulation machine,marumerizer, pelleter, and the like; a crushing granulation method usinga speed mill or the like to crush a wet mixture; another crushinggranulation method using a minimizer, power kneader, speed mill, or thelike; a tumbling granulation method making use of a phenomenon whichoccurs during rotation; and a fluidized-bed granulation method such as aspray-drying (the Japanese Pharmacopoeia A-73 to 74). Of these methods,the fluidized-bed granulation method is preferable for obtaining thebulky granular preparation of the present invention.

According to the fluidized-bed granulating method, powders are kept in afluid state, to which a solution containing a binder is sprayed forcohering and granulating the particles. In more detail, a binder issprayed onto a layer of floating powders from a nozzle attached to thegranulating apparatus for inducing cohesion of particles to allow themto grow into homogeneous particles.

By contrast, according to the tumbling method, powder is wetted, abinder is added thereto if necessary, and subsequently vibration orrotation movement is applied to make spherical particles due tocohesion. Granular preparations obtained by a method which producesgranules having a high apparent density, like this method, precipitatewhen they are added in water or in an aqueous medium. Such preparationsrequire a stirring time of at least 30 seconds and preferably 1 minuteor more for making a dispersion without causing coagulation, andtherefore, a very short stirring of 5 seconds or so as achieved in thepresent invention cannot provide a suspension. This is because granularpreparations having a high apparent density have less voids compared tothose having a low apparent density, and therefore, water or an aqueousmedium permeates into the granules slowly, causing slow hydration anddissolution of viscosity-increasing agents to further slow down thespeed of increase of the viscosity. Accordingly, if stirring isinsufficient, granules precipitate, form a gel at the bottom of thecontainer, and produce clusters which will no more be dispersed again.

By extrusion granulation, crushing granulation or by tumblinggranulation, particles undergo relatively strong shear stress orcompression stress during the granulation step, which results inunpreferable granules having a high apparent density.

The granular preparation of the present invention which can instantlyprovide a dispersion is preferably prepared by the combination offluidized-bed granulation and spray coating. More specifically, aferromagnetic material or ferromagnetic particles, which may be added atthe time of granulation, are preferably dispersed in an aqueous solutionof a viscosity-increasing agent or a binder, and the resultingdispersion may be sprayed for coating onto nuclei particles of additivesother than ferromagnetic particles obtained by fluidized-bed granulationin advance.

The thus-obtained granules have a low apparent density, do notprecipitate when added in water or in an aqueous medium, are instantlyand readily dispersed only by a stirring of 5 seconds or so withoutforming clusters or coagulation, and provide a viscous homogeneoussuspension with ease. Since granular preparations having a low apparentdensity have a lot of voids compared to granular preparations having ahigh apparent density, water or an aqueous medium can easily permeateinto the granular preparations. Accordingly, the viscosity-increasingagents contained therein can easily be hydrated or dissolved to quicklyelevate the viscosity of the system, achieving an instant dispersion bya stirring of 5 seconds or so without causing precipitation.Furthermore, the granular preparations having a low apparent densityaccording to the invention have a lot of voids, and therefore, clustersare hardly formed even though gelation occurs during dispersion.

EXAMPLES

The present invention will next be described more specifically by way ofexamples, comparative examples, and test example, which should not beconstrued as limiting the invention.

Using various viscosity-increasing agents, binders, vehicles anddisintegrants, the below described 9 preparations were prepared. Theformulations are shown in Table 1.

Comparative Example 1

15 g of polyvinylpyrrolidone (hereinafter referred to as PVP) wasdissolved in water in advance, and 3.0 g of ferromagnetic particles*were suspended therein. Water was added to make a total volume of 100ml, and thus a PVP binding solution containing ferromagnetic particleswas obtained. 48.0 g of xanthan gum, 84 g of lactose and 150 g of cornstarch were placed in a tumbling granulator, then the PVP bindingsolution containing ferromagnetic particles was added thereto forgranulation. The granules obtained were screened by the use of a sieveNo. 12, and those which did not pass the sieve were crushed and screenedagain by the use of a sieve No. 12, and combined with the previouslyobtained through-sieve granules. Screening of granules was performedagain using a sieve No. 42. Granules which passed through the No. 42sieve were removed to obtain a granular preparation. *: Theferromagnetic particles used in this example were prepared by suspendingsolid ferromagnetic particles in water with a proportion of 12 to 14%(hereinafter the same applies).

Comparative Example 2

2.5 g of hydroxypropylmethylcellulose (hereinafter referred to as HPMC)was dissolved in water in advance, and water was added thereto formaking a total volume of 83 ml to prepare an HPMC solution. 37.5 g ofcarboxymethylcellulose-Na (hereinafter referred to as CMC-Na), 37.5 g ofveegum, 100 g of lactose and 65 g of corn starch were placed in atumbling granulator, then the HPMC binding solution was added theretofor granulation. The granules obtained were screened by the use of asieve No. 12, and granules which remained on the sieve were crushed andscreened again by the use of a sieve No. 12 for combining with thepreviously obtained through-sieve granules. Screening of granules wasperformed again using a sieve No. 42. Granules which passed through theNo. 42 sieve were removed to obtain crude granules.

2.4 g of ferromagnetic particles was suspended in an aqueous solution of1.2 g of HPMC dissolved in water in advance, and 50 ml in total of aferromagnetic particle-containing coating solution was prepared. 116.4 gof the core granules were placed in a fluidized-bed granulator, and theferromagnetic particle-containing coating solution was sprayed thereto.Subsequently, granules were screened by the use of a No. 12 sieve, andgranules which did not pass through the sieve were removed to prepare agranular preparation containing ferromagnetic particles.

Comparative Example 3

2.5 g of HPMC was dissolved in water in advance, and water was addedthereto for making a total volume of 83 ml to prepare an HPMC bindingsolution. 75 g of methylcellulose (hereinafter referred to as MC), 100 gof lactose and 68.8 g of corn starch were placed in a tumblinggranulator, then the HPMC binding solution was added thereto forgranulation. The granules obtained were screened by the use of a sieveNo. 30, and granules which did not pass the sieve were crushed andscreened again by the use of a sieve No. 30 for combining with thepreviously obtained through-sieve granules. Screening of granules wasperformed again using a sieve No. 100. Granules which passed through theNo. 100 sieve were removed to obtain core granules.

1.2 g of ferromagnetic particles was suspended in an aqueous solutioncontaining 0.6 g of HPMC which had been dissolved in water in advance,thereby 25 ml in total of a ferromagnetic particle-containing coatingsolution was prepared. 118.2 g of the core granules were placed in afluidized-bed granulator, and the ferromagnetic particle-containingcoating solution was sprayed thereto. Thereafter, granules were screenedby the use of a No. 20 sieve, and granules which remained on the sievewere removed to prepare a granular preparation containing ferromagneticparticles.

Example 1

12.0 g of HPMC was dissolved in water in advance, and water was addedthereto to prepare an HPMC binding solution having a total volume of 200ml. 40.0 g of CMC-Na, 126 g of lactose, 16.0 g of hydroxypropylcellulosehaving a low substitution degree were placed in a fluidized-bedgranulator, then the HPMC binding solution was sprayed thereto forgranulation. The granules obtained were screened by the use of a sieveNo. 12, and granules which remained on the sieve were crushed in mortarand screened again by the use of a sieve No. 12 for combining with thepreviously obtained through-sieve granules to obtain core granules.

2.4 g of ferromagnetic particles was suspended in an aqueous solutioncontaining 1.2 g of HPMC which had been dissolved in water in advance,and 50 ml in total of a ferromagnetic particle-containing coatingsolution was prepared. 116.4 g of the core granules were placed in afluidized-bed granulator, and the ferromagnetic particle-containingcoating solution was sprayed thereto. Subsequently, granules werescreened by the use of a No. 12 sieve, and granules which did not passthrough the sieve were removed to prepare a granular preparationcontaining ferromagnetic particles.

Example 2

9.0 g of hydroxypropylcellulose (hereinafter referred to as HPC) wasdissolved in water in advance, in which 3.0 g of ferromagnetic particleswere suspended. Water was added thereto for making a total volume of 300ml to prepare a HPC binding solution containing ferromagnetic particles.30.0 g of xanthan gum, 90 g of crystallinecellulose.carboxymethylcellulose-Na (hereinafter referred to as AvicelRC-591), 18 g of lactose were placed in a fluidized-bed granulator, andthen the HPC binding solution containing ferromagnetic particles wassprayed thereto for granulation. The granules obtained were screened bythe use of a sieve No. 12, and granules which did not pass the sievewere crushed in mortar and screened again by the use of a sieve No. 12for combining with the previously obtained through-sieve granules toobtaining a granular preparation containing ferromagnetic particles.

Example 3

10.0 g of HPC was dissolved in water in advance, water was added theretoto make a total volume of 200 ml to prepare a HPC binding solutioncontaining HPC. 80.0 g of MC, 80.0 g of Avicel RC-591 and 18.0 g of cornstarch were placed in a fluidized-bed granulator, then the HPC bindingsolution was sprayed thereto for granulation. The granules obtained werescreened by the use of a sieve No. 12, and granules which did not passthe sieve were crushed in mortar and screened again by the use of asieve No. 12 for combining with the previously obtained through-sievegranules to obtain core granules.

4.0 g of ferromagnetic particles was suspended in an aqueous solution of2.0 g of HPC which had been dissolved in water in advance, and 80 ml intotal of a ferromagnetic particle-containing coating solution wasprepared. 94.0 g of the core granules was placed in a fluidized-bedgranulator, and the ferromagnetic particle-containing coating solutionwas sprayed thereto. Thereafter, granules were screened by the use of aNo. 12 sieve, and granules which did not pass through the sieve wereremoved to prepare a granular preparation containing ferromagneticparticles.

Comparative Example 4

1.0 g of ferromagnetic particles, 10.0 g of CMC-Na, 20.0 g of lactose,17.0 g of corn starch and 2.0 g of HPMC were homogeneously mixed in amortar.

Comparative Example 5

3.0 g of HPMC was dissolved in water in advance, and water was addedthereto to make a total volume of 100 ml to prepare a HPMC bindingsolution. 189 g of lactose and 108.0 g of corn starch were placed in atumbling granulator, and then the HPMC binding solution was addedthereto for granulation. The granules obtained were screened by the useof a sieve No. 12, and granules which did not pass the sieve werecrushed in mortar and screened again by the use of a sieve No. 12 forcombining with the previously obtained through-sieve granules. Screeningof granules was performed again using a sieve No. 42. Granules whichpassed through the No. 42 sieve were removed to obtain core granules.

2.4 g of ferromagnetic particles was suspended in an aqueous solution of1.2 g of HPMC which had been dissolved in water in advance, and 50 ml intotal of a ferromagnetic particle-containing coating solution wasprepared. 116.4 g of the core granules was placed in a fluidized-bedgranulator, and the ferromagnetic particle-containing coating solutionwas sprayed thereto. Thereafter, granules were screened by the use of aNo. 12 sieve, and granules which did not pass through the sieve wereremoved to prepare a granular preparation containing ferromagneticparticles.

Comparative Example 6

6.0 g of HPMC was dissolved in water in advance, to which 3.0 g offerromagnetic particles were suspended. Water was added thereto to makea total volume of 200 ml to prepare a HPMC binding solution containingferromagnetic particles. 90.0 g of lactose and 51.0 g of corn starchwere placed in a fluidized-bed granulator, then the HPMC bindingsolution containing ferromagnetic particles was sprayed for granulation.The granules obtained were screened by the use of a sieve No. 12, andgranules which did not pass the sieve were crushed in mortar andscreened again by the use of a sieve No. 12 for combining with thepreviously obtained through-sieve granules to obtain a granularpreparation containing ferromagnetic particles.

                                      TABLE 1                                     __________________________________________________________________________    Amounts of components in Examples and Reference Examples                                   1   2   3               7   8   9                                Granulation method                                                                         Tumble                                                                            Tumble                                                                            Tumble                                                                            4   5   6   Mortar                                                                            Tumble                                                                            Fluid                            Examples     Comp.                                                                             Comp.                                                                             Comp.                                                                             Fluid                                                                             Fluid                                                                             Fluid                                                                             Comp.                                                                             Comp.                                                                             Comp.                            (Comparative Examples)                                                                     Ex. 1                                                                             Ex. 2                                                                             Ex. 3                                                                             Ex. 1                                                                             Ex. 2                                                                             Ex. 3                                                                             Ex. 4                                                                             Ex. 5                                                                             Ex.6                             __________________________________________________________________________    Timing of adding                                                                           During                                                                            During                                                                            During                                                                            During                                                                            During                                                                            During                                                                            During                                                                            During                                                                            During                           ferromagnetic                                                                              granu-                                                                            coat-                                                                             coat-                                                                             coat-                                                                             granu-                                                                            coat-                                                                             mortar                                                                            coat-                                                                             granu-                           particles    lation                                                                            ing ing ing lation                                                                            ing     ing lation                                        Amounts of components (upper row: mg, lower row: %)              Ferromagnetic                                                                              100 100 100 100 100 100 100 100 100                              particles    1   2   1   2   2   4   2   2   2                                Thickener                                                                            Xanthan                                                                             1600            1000    1000                                            gum   16              20      20                                              CMC(Na)   750     1000                                                                  15      20                                                          Methyl-                   1000                                                cellulose                 40                                                  Crystalline   3000    3000                                                                              1000                                                cellulose     30      60  40                                                  CMCNa                                                                         Veegum    750                                                                           15                                                           Binder HPC                   300 175                                                                       6   7                                                   HPMC      100 150 350         200 100 200                                               2   1.5 7           4   2                                           PVP   500                                                                           5                                                                Vehicle                                                                              Lactose                                                                             2800                                                                              2000                                                                              4000                                                                              3150                                                                              600     2000                                                                              3000                                                                              3000                                          28  40  40  63  12      40  60  60                                      Corn starch                                                                         5000                                                                              1300                                                                              2750        225 1700                                                                              1800                                                                              1700                                          50  26  27.5        9   34  38  34                               Disinte-                                                                             HPC of low        400                                                  grant  substitution      8                                                           degree                                                                 Total (mg)   10000                                                                             5000                                                                              10000                                                                             5000                                                                              5000                                                                              2500                                                                              5000                                                                              5000                                                                              5000                             __________________________________________________________________________     CMC(Na); carboxymethylcellulose (sodium): HPC; hydroxypropylcellulose:        HPMC; hydroxypropylmethylcellulose: PVP; polyvinylpyrrolidone: Tumble;        tumbling granulation method: Fluid; fluidizedbed granulation method:          Mortar; mortar mixing method: During mortar; during mortar mixing        

Test Example 1 (Measurement of particle size distribution)

20 g each of the granular preparations or mortar mixtures prepared inExamples 1-3 and Comparative Examples 1-6 was classified using a 12 meshsieve and a 100 mesh sieve set on a sieve shaker (Ro-tap shaker,trademark) for 5 minutes. Based on the proportion by weight of theclassified particles, a particle size distribution was obtained. Theparticle size distribution of the granules obtained in Examples 1-3 andComparative Examples 1-3; 5-6 was such that granules having a diameterof 150 to 1400 μm were present in a proportion of not less than 90%(Table 2). By contrast, the particle size distribution of the mixtureobtained in Comparative Example 4, which were prepared by mixingferromagnetic particles and additives in mortar was such that powdershaving a diameter of less than 150 μm were present in a proportion ofnot less than 99%.

                  TABLE 2                                                         ______________________________________                                        Distribution of particle size                                                 Diam-                                                                         eter                                                                          of    Distribution of particle size (%)                                       parti-                                                                              Comparative               Comparative                                   cles  Examples     Examples     Examples                                      μm 1      2      3    1    2    3    4    5    6                           ______________________________________                                        1400- 100    100    99.6 97.4 97   93.2  0.7 99.3 98.6                        150                                                                           150 or                                                                               0      0      0.4  2.6  3    6.8 99.3  0.7  1.4                        less                                                                          ______________________________________                                         Note: 1400 μm corresponds to Mesh No. 12, and 150 μm corresponds to     Mesh No. 100.                                                            

Test Example 2 (Measurement of the apparent density)

15 g each of granular preparations obtained in Examples 1-3 andComparative Examples 1, 2, 3, 5 and 6 and a mortar mixture obtained inComparative Example 4 was taken and placed in a 100 ml messcylinder,respectively, and then the messcylinder was attached to a tappingmachine. After tapping 200 times, the surface of the sample in themesscylinder was made flat by the use of a spatula, and the volume ofthe sample was visually read. The apparent density was calculatedaccording to the following equation:

    Apparent density=(Quantity of sample (15 g))/(Apparent volume (ml))

The apparent densities of the particles of the granular preparationsprepared in Examples 1-3 and Comparative Example 6, which were preparedby a fluidized-bed granulation method were all not more than 0.4 g/ml.By contrast, the apparent densities of the particles of the granularpreparations prepared in Comparative Examples 1, 2, 3 and ComparativeExample 5, which were prepared by a tumbling granulation method were allnot less than 0.5 g/ml. The apparent density of the mortar mixtureobtained in Comparative Example 4 which was not granulated was 0.77g/ml.

Test Example 3 (Measurement of viscosity)

A granular preparation in an amount equivalent to 100 mg offerromagnetic particles was dispersed in 200 ml of water. After allowingit to stand overnight, the dispersion which presented a homogeneoussuspension was subjected to viscosity measurement using a B-typeviscometer in a temperature range of 18° to 22° C. at 60 rpm. SpindleNo. 3 was used for measuring the viscosity of the suspensions preparedwith Examples 1-3 granular preparations and Comparative Examples 1-4granular preparations, and spindle No.1 was used for measuring theviscosity of the suspensions prepared with Comparative Examples 5 and 6preparations. Those which were granulated together withviscosity-increasing agents, namely those using Examples 1-3 andComparative Examples 1-3 preparations exhibited 200 to 2000 cp(centipoises). Use of Comparative Example 4 preparation also exhibited asimilar value (Table 3). Use of preparations of Comparative Examples 5and 6 which did not contain a viscosity-increasing agent exhibited notmore than 5 cp.

                                      TABLE 3                                     __________________________________________________________________________    Comparison of apparent density and viscosity                                  Comparative                  Comparative                                      Examples         Examples    Examples                                         1        2   3   1   2   3   4   5  6                                         __________________________________________________________________________    Apparent                                                                           0.77                                                                              0.71                                                                              0.50                                                                              0.26                                                                              0.30                                                                              0.16                                                                              0.77                                                                              0.53                                                                             0.34                                      density                                                                       (g/ml)                                                                        Viscosity                                                                          558 266 1960                                                                              278 964 280 262 4.2                                                                              1.5                                       (cp)                                                                          __________________________________________________________________________

Test Example 4 (Aggregation of particles during preparation of asolution to be administered)

A granular preparation in an amount equivalent to 100 mg offerromagnetic particles was added to 100 ml of water, followed byimmediate stirring with a spatula for 1 minute. The presence or absenceof aggregation of particles was visually observed. When the preparationsof Examples 1-3 and Comparative Examples 1-3 were used, no aggregationwas observed during preparation of a solution (Table 4).

Aggregation of particles was observed when a Comparative Example 4preparation which contained a viscosity-increasing agent but was notgranulated was used. Moreover, no aggregation was observed when thegranular preparations of Comparative Examples 5 and 6 which did notcontain a viscosity-increasing agent were used.

                  TABLE 4                                                         ______________________________________                                        Aggregation of particles during preparation of                                a solution to be administered                                                 Comparative                Comparative                                        Examples      Examples     Examples                                           1       2      3      1    2    3    4     5    6                             ______________________________________                                        Agg- None   None   None None None None Obser-                                                                              None None                        rega-                                  ved                                    tion                                                                          of                                                                            parti-                                                                        cles                                                                          ______________________________________                                    

Test Example 5 (Time required for preparing a suspension to beadministered in which precipitation is not observed)

A granular preparation in an amount equivalent to 100 mg offerromagnetic particles was added to 200 ml of water, followed byimmediate stirring with a spatula for 5 seconds for dispersion.Precipitation of particles was observed for 1 minute. When precipitationwas observed, a granular preparation in an amount equivalent to 100 mgof ferromagnetic particles was separately added to 200 ml of water, andstirred for a prolonged period of time until precipitation is no moreobserved. The stirring time which was required for observing noprecipitation was taken as "time A", which was counted for the period oftime required for preparing a solution to be administered. Among thepreparations of Examples 1-3 and Comparative Examples 1-3, which weregranulated together with a viscosity-increasing agent, the time A forpreparations of Comparative Examples 1-3 obtained by a tumblinggranulation method was 70 to 90 seconds, whereas time A for preparationsof Examples 1-3 obtained by a fluidized-bed granulation method was shortand 5 seconds (Table 5). The preparation of Comparative Example 4 whichcontained a viscosity-increasing agent but was not granulated formedaggregation of particles at the time of preparing a solution to beadministered and therefore, measurement was not possible.

Test Example 6 (Time required for suspending)

A granular preparation in an amount equivalent to 20 mg of ferromagneticparticles was taken and dispersed in 40 ml of water. The resultingdispersion was shaken with a shaking apparatus. The period of timeduring which particles are uniformly suspended and can no more bevisually observed was defined as the time required for suspending. InExamples 1 to 3 where granules containing a viscosity-increasing agentwere prepared by a fluidized-bed method, the resulting granulesexhibited shorter the time required for suspending (measured by shakingtime with a shaking apparatus), compared to those obtained inComparative Examples 1 to 3 which employed a tumbling granulation method(Table 5).

                  TABLE 5                                                         ______________________________________                                        Comparison of preparation time                                                Comparative                 Comparative                                       Examples       Examples     Examples                                          1        2      3      1    2    3    4    5    6                             ______________________________________                                        Time A                                                                              Time (seconds)                                                                70     80     90   5    5    5    *    640  10                          Time B                                                                              Time (minutes)                                                                11     12      8   4    4    7    20    10   1                          ______________________________________                                         Time A: Period of time (seconds) of stirring required until precipitation     of particles is no more observed.                                             Time B: Period of time (minutes) required for preparing a homogeneous         suspension.                                                                   *Measurement could not be carried out due to aggregation. Preparations of     Comparative Examples 1, 2 and 3 were prepared by tumbling granulation         method, and Preparations of Examples 1, 2 and 3 were prepared by              fluidizedbed granulation method.                                         

Test Example 7 (Suspension Stability)

A granular preparation in an amount equivalent to 100 mg offerromagnetic particles was taken and dispersed in 200 ml of water.After allowing it to stand overnight, a homogeneous suspension wasstirred with a spatula. The state of suspension was observed after 30minutes and 24 hours. The suspensions using preparations of Examples 1-3and Comparative Examples 1-4 which contained a viscosity-increasingagent exhibited an excellent suspension stability. By contrast, thesuspensions using preparations of Comparative Examples 5 and 6 which didnot contain a viscosity-increasing agent were both separated in 30minutes (Table 6).

                  TABLE 6                                                         ______________________________________                                        Suspension stability of suspensions                                           Comparative                 Comparative                                       Examples       Examples     Examples                                          1        2      3      1    2    3    4    5    6                             ______________________________________                                        After Good   Good   Good Good Good Good Good Sepa-                                                                              Sepa-                       30                                           rated                                                                              rated                       minutes                                                                       After Good   Good   Good Good Good Good Good Sepa-                                                                              Sepa-                       24                                           rated                                                                              rated                       hours                                                                         ______________________________________                                         Good; Stable, and homogeneous suspension was maintained.                      Separated: Poor stability, and precipitation was observed.               

Industrial Applicability

The granular preparation of the present invention provides a stable,viscous, and uniform dispersion which does not cause precipitation ofparticles by a mere stirring/suspending of the preparation in water orin an aqueous medium. The granular preparation of the invention does notform clusters at the time of suspending. In addition, it provides asuspension which is suitable for administering to human subjects andwhich can be instantly prepared.

Since the present preparation is in a solid form, it is free fromputrefaction due to microorganisms and molds compared with aqueousdispersions, and is advantageous in handling from the aspects oftransportation and storage space.

Accordingly, the granular preparation of the present invention is veryuseful as an negative contrast agent for MRI which is dosed orally orper rectum and prepared into a suspension upon use.

We claim:
 1. A granular preparation for magnetic resonance imaging, comprising bulky granules which contain a ferromagnetic material and a viscosity-increasing agent,wherein the apparent density of the granules is not more than 0.4 g/ml.
 2. The granular preparation according to claim 1, which immediately disperses in water or in an aqueous medium when mixed therewith to provide a uniform viscous aqueous suspension.
 3. The granular preparation according to claim 1, which is prepared by a fluidized-bed granulation method or by a combination of a fluidized-bed granulation method and a spray-coating method.
 4. The granular preparation according to claim 1, wherein the ferromagnetic material exhibits ferromagnetism, ferrimagnetism or superparamagnetism.
 5. The granular preparation according to claim 1, wherein the ferromagnetic material is in the form of a particle which is coated by, embedded into or carried by a non-magnetic polymer.
 6. The granular preparation according to claim 1, wherein the ferromagnetic material is selected from the group consisting of magnetite (Fe₃ O₄), gamma-ferric oxide (gamma-Fe₂ O₃), cobalt ferrite, nickel ferrite, manganese ferrite and mixtures thereof.
 7. The granular preparation of claim 5, wherein said ferromagnetic particles have an average diameter of 0.1 to 20 μm.
 8. The granular preparation of claim 1, comprising 1-10% by weight of said ferromagnetic material, based on the total weight of the preparation.
 9. The granular preparation of claim 1, comprising 15-80% by weight of said viscosity-increasing agent, based on the total weight of the preparation.
 10. The granular preparation of claim 1, further comprising at least one member selected from the group, consisting of disintegrants, binders, vehicles and surfactants.
 11. The granular preparation of claim 1, wherein the apparent density of the granules is 0.1-0.4 g/ml.
 12. The granular preparation of claim 1, wherein said granules have a particle diameter of 150-1,400 μm.
 13. The granular preparation of claim 12, wherein said granules having a diameter of not more than 150 μm exist in a proportion of not more than 20% of the total particles. 